Malaria is a protozoan disease transmitted by mosquitoes. It is caused by Plasmodium parasites and affects over 3 billion people worldwide, causing approximately 1,200 deaths per day. The most severe form is caused by P. falciparum. Malaria symptoms include fever, chills, vomiting and headaches. Severe malaria can involve cerebral malaria, hypoglycemia, acidosis, pulmonary edema, renal failure and other complications affecting multiple organ systems. Malaria in pregnancy poses risks of low birth weight, stillbirth and maternal mortality.

1. MALARIA

2. • Malaria is a protozoan disease transmitted by
the bite of infected female Anopheles
mosquitoes.

3. EPIDEMIOLOGY
• Six species of the genus Plasmodium cause nearly all
malarial infections in humans.
• These are
– P. falciparum,
– P. vivax,
– two morphologically identical species of P. ovale (curtisi and
wallikeri),
– P. malariae,
– P. knowlesi
While almost all deaths are caused by falciparum malaria,
P. knowlesi and occasionally P. vivax can also cause severe illness.

4. • most important of the parasitic diseases of humans,
malaria is transmitted in 91 countries containing 3
billion people and causes ~1200 deaths each day.
• Mortality rates have decreased dramatically over the
past 15 years.
• Malaria was eliminated from the United States,
Canada, Europe, and Russia >50 years ago, but its
prevalence rose in many parts of the tropics between
1970 and 2000.
• Malaria remains today, as it has been for centuries, a
heavy burden on tropical communities, a threat to
nonendemic countries, and a danger to travelers.

5. ETIOLOGY & PATHOGENESIS
• Human infection begins when a female anopheline
mosquito inoculates plasmodial sporozoites from its
salivary glands during a blood meal
• These microscopic motile forms of the malaria parasite
are carried rapidly via the bloodstream to the liver,
where they invade hepatic parenchymal cells and begin
a period of asexual reproduction.
• By this amplification process (known as intrahepatic or
preerythrocytic schizogony), a single sporozoite may
produce from 10,000 to >30,000 daughter merozoites.
• The swollen infected liver cells eventually burst,
discharging motile merozoites into the bloodstream.

6. • These merozoites then invade red blood cells (RBCs) to
become trophozoites and multiply six- to twenty fold every
48 h (P. knowlesi, 24 h; P. malariae, 72 h).
• When the parasites reach densities of ~50/μL of blood
(~100 million parasite in the blood of an adult), the
symptomatic stage of the infection begins.
• In P. vivax and P. ovale infections, a proportion of the intra
hepatic forms do not divide immediately but remain inert
for a period ranging from 2 weeks to ≥1 year.
• These dormant forms, or hypnozoites, are the cause of the
relapses that characterize infection with these species.

7. • The brunt of malarial infection is borne by
RBCs, which get infected and lose their
deformability and get hemolysed.

8. • During the first few hours of intraerythrocytic
development, the small “ring forms” of the different
malaria species appear similar under light microscopy.
• As the trophozoites enlarge, species-specific characteristics
become evident malaria pigment (hemozoin) becomes
visible, and the parasite assumes an irregular or ameboid
shape.
• By the end of the intra erythrocytic life cycle, the parasite
has consumed two-thirds of the RBC’s hemoglobin and has
grown to occupy most of the cell. It is now called a schizont.
• Multiple nuclear divisions have taken place (schizogony or
merogony).
• The infected RBC then ruptures to release 6–30 daughter
merozoites, each potentially capable of invading a new RBC
and repeating the cycle.

9. • After being ingested in the blood meal of a biting
female anopheline mosquito, the male and female
gametocytes fuse to form a zygote in the insect’s
midgut.
• This zygote matures into an ookinete, which penetrates
and encysts in the mosquito’s gut wall. The resulting
oocyst expands by asexual division until it bursts to
liberate myriad motile sporozoites, which then migrate
in the hemolymph to the salivary gland of the
mosquito to await inoculation into another human at
the next feed, thus completing the life cycle.

11. PATHOPHYSIOLOGY
• ERYTHROCYTE CHANGES
• After invading an erythrocyte, the growing malarial
parasite progressively consumes and degrades
intracellular proteins, principally hemoglobin.
• The potentially toxic heme is detoxified by lipid-
mediated crystallization to biologically inert hemozoin
(malaria pigment).
• The parasite also alters the RBC membrane by changing
its transport properties, exposing cryptic surface
antigens, and inserting new parasite-derived proteins.
• The RBC becomes more irregular in shape, more
antigenic, and less deformable.

12. • In P. falciparum infections, membrane protuberances appear on
the erythrocyte’s surface 12–15 h after the cell’s invasion.
• These “knobs” extrude a high-molecular-weight, antigenically
variant, strain-specific erythrocyte membrane adhesive protein
(PfEMP1) that mediates attachment to receptors on venular and
capillary endothelium (cytoadherence).
• Erythrocytes containing more mature parasites stick inside and
eventually block capillaries and venules.
• These infected RBCs may also adhere to uninfected RBCs (to
form rosettes) and to other parasitized erythrocytes
(agglutination). The processes of cytoadherence, rosetting, and
agglutination are central to the pathogenesis of falciparum
malaria.

13. • They result in the sequestration of infected RBCs in
vital organs (particularly the brain), where they
interfere with microcirculatory flow and metabolism.
• Sequestered parasites continue to develop out of reach
of the principal host defense mechanism: splenic
processing and filtration.
• As a consequence, only the younger ring forms of the
asexual parasites are seen circulating in the peripheral
blood in falciparum malaria, and the level of peripheral
parasitemia underestimates the true number of
parasites within the body.

14. • HOST RESPONSE
• Initially, the host responds to malaria infection by
activating nonspecific defense mechanisms.
• Splenic immunologic and filtrative clearance functions
are augmented, and the removal of both parasitized
and uninfected erythrocytes is accelerated.
• The spleen also removes damaged ring-form parasites
(a process known as “pitting”) and returns the once-
infected erythrocytes to the circulation, where their
survival is shortened.
• The parasitized cells escaping splenic removal are
destroyed when the schizont ruptures.

15. • Temperatures of ≥40°C (≥104°F) damage mature
parasites; in untreated infections, the effect of
such temperatures is to further synchronize the
parasitic cycle, with eventual production of the
regular fever spikes and rigors that originally
characterized the different malarias.
• These regular fever patterns (quotidian, daily;
tertian, every 2 days; quartan, every 3 days) are
sel- dom seen today as patients receive prompt
and effective antimalarial treatment.

16. • HbA/S heterozygotes (sickle cell trait) have a sixfold
reduction in the risk of dying from severe falciparum
malaria and are correspondingly pro tected from bacterial
infections that complicate malaria.
• Hemoglobin S–containing RBCs impair parasite growth at
low oxygen tensions, and
• P. falciparum–infected RBCs containing hemoglobin S or C
exhibit reduced cytoadherence because of reduced surface
presentation of the adhesin PfEMP1.
• Parasite multiplication in HbA/E heterozygotes is reduced at
high parasite densities.
• Children with α-thalassemia have more frequent malaria
(both vivax and falciparum) in the early years of life

17. • exposure to sufficient strains confers protection from high-
level parasitemia and disease but not from infection.
• As a result of this state of infection without illness
(premunition), asymptomatic parasitemia is very common
among adults and older children living in regions with
stable and intense transmission (i.e., holo- or
hyperendemic areas) and also in parts of low-transmission
areas.
• Several factors retard the development of cellular immunity
to malaria. These factors include the absence of major
histocompatibility antigens on the surface of infected RBCs,
which precludes direct T cell recognition; malaria antigen–
specific immune unresponsiveness; and the enormous
strain diversity of malarial parasites,

18. CLIINICAL FEATURES
• Malaria is a common cause of fever in tropical countries.
• The first symptoms of malaria are non specific; the lack of a
sense of well-being, headache, fatigue, abdominal
discomfort, and muscle aches followed by fever are all
similar to the symptoms of a minor viral illness.
• In some instances, a prominence of headache, chest pain,
abdominal pain, cough, arthralgia, myalgia, or diarrhea may
suggest another diagnosis.
• Although headache may be severe in malaria, the neck
stiffness and photophobia seen in meningitis do not occur.
• Nausea, vomiting, and orthostatic hypotension are
common.

19. • The classic malarial paroxysms, in which fever spikes, chills,
and rigors occur at regular intervals, are relatively unusual
and suggest infection (often relapse) with P. vivax or P.
ovale.
• The fever is usually irregular at first (that of falciparum
malaria may never become regular).
• The temperature of nonimmune individuals and children
often rises above 40°C (104°F), with accompanying
tachycardia and sometimes delirium.
• febrile convulsions may occur with any of the malarias,
generalized seizures are associated specifically with
falciparum malaria and may herald the development of
encephalopathy (cerebral malaria).

20. • In nonimmune individuals with acute malaria, the spleen
takes several days to become palpable, but splenic
enlargement is found in a high proportion of otherwise
healthy individuals in malaria-endemic areas and reflects
repeated infections.
• Enlargement of the liver is also common, particularly
among young children.
• Mild jaundice is common among adults and usually
resolves over 1–3 weeks.
• Malaria is not associated with a rash.
• Petechial hemorrhages in the skin or mucous membranes
only very rarely in severe falciparum malaria.

21. • SEVERE FALCIPARUM MALARIA
• uncomplicated falciparum malaria (i.e., that in which
the patient can sit or stand unaided and can swallow
medicines and food) carries a mortality rate of <0.1%.
• CEREBRAL MALARIA
• Coma is a characteristic and ominous feature of
falciparum malaria and, even with treatment, has been
associated with death rates of ~20% among adults and
15% among children.
• The onset of coma may be gradual or sudden following
a convulsion.

22. • Cerebral malaria manifests as diffuse symmetric encephalopathy;
• Passive resistance to head flexion may be detected, signs of
meningeal irritation are absent.
• The eyes may be divergent, and bruxism and a pout reflex are
common,
• The corneal reflexes are preserved, except in deep coma.
• Muscle tone may be either increased or decreased.
• The tendon reflexes are variable, and the plantar reflexes may be
flexor or extensor; the abdominal and cremasteric reflexes are
absent.
• Flexor or extensor posturing may be seen.
• 15% of patients have retinal hemorrhages, include discrete spots of
retinal opacification (30–60%), papilledema (8% among children,
rare among adults), cotton wool spots (<5%), and decolorization of
a retinal vessel or segment of vessel.

23. • seizure activity is common, particularly among
children, and may manifest as repetitive tonic–clonic
eye movements or even hypersalivation.
• Whereas adults rarely (<3% of cases) suffer neurologic
sequelae, ~10% of children surviving cerebral
malaria—especially those with hypoglycemia, severe
anemia, repeated seizures, and deep coma—have
residual neurologic deficits; hemiplegia, cerebral palsy,
cortical blindness, deafness, and impaired cognition
may occur.
• ~10% of children surviving cerebral malaria have a
persistent language deficit

24. • HYPOGLYCEMIA
• Hypoglycemia, an important and common
complication of severe malaria, is associated with a
poor prognosis and is particularly problematic in
children and pregnant women.
• Hypoglycemia in malaria results from a failure of
hepatic gluconeogenesis and an increase in the
consumption of glucose by both the host and, to a
much lesser extent, the malaria parasites.
• Hyperinsulinemic hypoglycemia is especially
troublesome in pregnant women receiving quinine
treatment.

25. • ACIDOSIS
• Acidosis is an important cause of death from severe malaria and
results from accumulation of organic acids.
• Hyperlactatemia commonly coexists with hypoglycemia.
• coexisting renal impairment often compounds acidosis.
• Acidotic breathing, sometimes called “respiratory distress,” is a sign
of poor prognosis.
• It is followed often by circulatory failure refractory to volume
expansion or inotropic drug treatment and ultimately by respiratory
arrest.
• Lactic acidosis is caused by the combination of anaerobic glycolysis
in tissues where sequestered parasites interfere with micro
circulatory flow, lactate production by the parasites, and a failure of
hepatic and renal lactate clearance.

26. • NONCARDIOGENIC PULMONARY EDEMA
• Adults with severe falciparum malaria may
develop noncardiogenic pulmonary edema
even after several days of antimalarial
therapy.
• Pathogenesis of this variant of the adult
respiratory distress syndrome is unclear.
• Pulmonary edema can be precipitated by
overly vigorous administration of IV fluid.

27. • RENAL IMPAIRMENT
• Acute kidney injury is common in severe falciparum
malaria. The pathogenesis of renal failure is unclear
but may be related to erythrocyte sequestration and
agglutination interfering with renal microcirculatory
flow and metabolism.
• In survivors, urine flow resumes in a median of 4 days,
and serum creatinine levels return to normal in a mean
of 17 days. Early dialysis or hemofiltration considerably
enhances the likelihood of a patient’s survival.

28. • HEMATOLOGIC ABNORMALITIES
• Anemia results from accelerated RBC removal by the
spleen, obligatory RBC destruction at parasite schizogony,
and ineffective erythropoiesis.
• Splenic clearance of all RBCs is increased.
• Acute hemolytic anemia with massive hemoglobinuria
(“blackwater fever”) may occur.
• Hemoglobinuria may contribute to renal injury.
• Slight coagulation abnormalities are common in falciparum
malaria, and mild thrombocytopenia is usual
• Hematemesis from stress ulceration or acute gastric
erosions also may occur rarely.

29. • LIVER DYSFUNCTION
• Mild hemolytic jaundice is common in malaria.
Severe jaundice is associated with P. falciparum
infections; is more common among adults than
among children; and results from hemolysis,
hepatocyte injury, and cholestasis.
• When accompanied by other vital-organ
dysfunction (often renal impairment), liver
dysfunction carries a poor prognosis.
• Hepatic dysfunction contributes to hypoglycemia,
lactic acidosis, and impaired drug metabolism.

30. • OTHER COMPLICATIONS
• HIV/AIDS and malnutrition predispose to more severe
malaria in nonimmune individuals. Malaria anemia is
worsened by concurrent infections with intestinal
helminths, hookworm in particular.
• Septicemia may complicate severe malaria, particularly
in children.
• Chest infections and catheter-induced urinary tract
infections are common among patients who are
unconscious for >3 days.
• Aspiration pneumonia may follow generalized
convulsions.

33. MALARIA IN PREGNANCY
• Malaria in early pregnancy causes fetal loss.
• associated with low birth weight (average reduction,
~170 g) and consequently increased infant mortality
rates.
• Maternal HIV infection predisposes pregnant women
to more frequent and higher-density malaria
infections, predisposes their newborns to congenital
malarial infection, and exacerbates the reduction in
birth weight associated with malaria.
• Fetal distress, premature labor, and stillbirth or low
birth weight are common results. Fetal death is usual in
severe malaria.

34. MALARIA IN CHILDREN
• Convulsions, coma, hypoglycemia, metabolic
acidosis, and severe anemia are relatively
common among children with severe malaria,
whereas deep jaundice, oliguric acute kidney
injury, and acute pulmonary edema are unusual.
• Severely anemic children may present with
labored deep breathing.
• children tolerate antimalarial drugs well and
respond rapidly to treatment.

35. TRANSFUSION MALARIA
• Malaria can be transmitted by blood
transfusion, needlestick injury, or organ
transplantation.
• The incubation period in these settings is
often short because there is no
preerythrocytic stage of development

36. DIAGNOSIS OF MALARIA
• Thick and thin blood smears should be prepared and
examined immediately to confirm the diagnosis and
identify the species of infecting parasite.
• If the blood smear is negative when examined by an
stains, Giemsa at pH 7.2 is preferred; Field’s, Wright’s,
or Leishman’s stain can also be used.
• Staining of parasites with the fluorescent dye acridine
orange allows more rapid diagnosis of malaria.
• The thin blood smear should be air-dried, fixed in
anhydrous methanol, and stained; the RBCs in the tail
of the film should then be examined under oil
immersion.

37. • The thick blood film should be of uneven
thickness.
• The smear should be dried thoroughly and
stained without fixing.
• As many layers of erythrocytes overlie one
another and are lysed during the staining
procedure, the thick film has the advantage of
concentrating the parasites and thus
increasing diagnostic sensitivity.

38. • Rapid, simple, sensitive, and specific antibody-
based diagnostic stick or card tests that detect P.
falciparum–specific, histidine-rich protein 2
(PfHRP2), lactate dehydrogenase, or aldolase
antigens finger-prick blood samples are now
being used.
• PfHRP2-based tests may remain positive for
several weeks after acute infection
• A disadvantage of rapid tests is that they do not
quantify parasitemia.

39. TREATMENT
• Patients with severe malaria and those unable
to take oral drugs should receive parenteral
antimalarial therapy immediately.
• The World Health Organization (WHO)
recommends artemisinin based combination
therapy (ACT) as first-line treatment for
uncomplicated falciparum malaria in malaria-
endemic areas

40. • SEVERE MALARIA
• In large randomized controlled clinical trials, parenteral artesunate,
a water-soluble artemisinin derivative, has reduced mortality rates
in severe falciparum malaria among Asian adults and children by 5%
and among African children by 22.5% compared with quinine
treatment.
• Artesunate therefore is now the drug of choice for all patients with
severe malaria everywhere. Artesunate is given by IV injection but
is also absorbed rapidly following IM injection.
• A rectal formulation of artesunate has been developed as a
community-based pre-referral treatment for patients in the rural
tropics who cannot take oral medications.
• Pre-referral administra- tion of rectal artesunate has been shown to
decrease mortality rates among severely ill children without access
to immediate parenteral treatment

41. • Parenteral quinidine is potentially dangerous and must be
closely monitored if dysrhythmias and hypotension are to
be avoided.
• Quinine is safer than quinidine;cardiovascular monitoring
is not required except when the recipient has cardiac
disease.
• Severe falciparum malaria constitutes a medical emergency
requiring intensive nursing care and careful management.
• Frequent evaluation of the patient’s condition is essential.
• In acute renal failure or severe metabolic acidosis,
hemofiltration or hemodialysis should be started as early as
possible

42. • Adjunctive treatments such as high-dose glucocorticoids,
urea, heparin, dextran, desferrioxamine, antibody to tumor
necrosis factor α, high-dose phenobarbital (20 mg/kg),
mannitol, or large-volume fluid or albumin boluses have
proved either ineffective or harmful in clinical trials and
should not be used.
• In severe malaria, parenteral antimalarial treatment should
be started immediately.
• Artesunate, given by either IV or IM injection, is the
treatment of choice; it is simple to administer, very safe,
and rapidly effective.
• It does not require dose adjustments in liver dysfunction or
renal failure. It should be used in pregnant women with
severe malaria.

43. • If artesunate is unavailable and artemether, quinine, or
quinidine is used, an initial loading dose must be given so
that therapeutic concentrations are reached as soon as
possible.
• Both quinine and quinidine will cause dangerous
hypotension if injected rapidly; when given IV, they must be
administered carefully by rate-controlled infusion only. If
this approach is not possible, quinine may be given by deep
IM injections into the anterior thigh.
• Convulsions should be treated promptly with IV (or rectal)
benzodiazepines.
• a full loading dose of phenobarbital (20 mg/kg) to prevent
convulsions should not be given as it may cause respiratory
arrest.

44. • When the patient is unconscious, the blood glucose level should
be measured every 4–6 h.
• All patients should receive a continuous infusion of dextrose, and
blood concentrations ideally should be maintained above 4
mmol/L.
• Hypoglycemia (<40 mg/dL) should be treated immediately with
bolus glucose.
• The parasite count and hematocrit should be measured every 6–
12h.
• Anemia develops rapidly; if the hematocrit falls to <20%, whole
blood (preferably fresh) or packed cells should be transfused
slowly.
• Renal function should be checked at least daily.

45. • Management of fluid balance is difficult in severe
malaria, particularly in adults, because of the thin
dividing line between overhydration (leading to
pulmonary edema) and underhydration
(contributing to renal impairment).
• Nasogastric feeding should be delayed in non-
intubated patients (for 60 h in adults and 36 h in
children) to reduce the risk of aspiration
pneumonia.

48. SCRUB TYPHUS

49. INTRODUCTION
• Rickettsiae are a heterogeneous group of
small, obligately intracellular, gram-negative
coccobacilli and short bacilli, most of which
aretransmitted by a tick, mite, flea, or louse
vector.
• O. tsutsugamushi differs substantially from
Rickettsia species both genetically and in cell
wall composition (i.e., it lacks
lipopolysaccharide).

50. • O. tsutsugamushi is maintained by transovarial
transmission in trombiculid mites or feeding on
infected rodents.
• After hatching, infected larval mites (chiggers, the
only stage that feeds on a host) inoculate
organisms into the skin.
• Infected chiggers are particularly likely to be
found in areas of heavy scrub vegetation during
the wet season, when mites lay eggs.

51. CLINICAL MANIFESTATIONS
• Illness varies from mild and self limiting to fatal.
• Incubation period of 6–21 days
• Onset is by fever, headache, chills, malaise, myalgia,
cough.
• Some patients recover spontaneously after a few days
• Classic case description includes an eschar(papule
appears which evolves in flat black eschar) where the
chigger has fed, regional lymphadenopathy, and a
maculopapular rash.
• Eschar resembles skin burn by cigarette butt without
signs of inflamation.

52. • Rash is difficult to identify in Indian population because
of dark skin.
• Fewer than 50% of Westerners develop an eschar, and
fewer than 40% develop a rash
• About 2/3rd of patients have GI symptoms like nausea,
diarrhea, vomiting.
• Among 1/3rd of patients develop Acute Kidney Injury.
• Severe cases typically manifest with encephalitis and
interstitial pneumonia due to vascular injury.
• Untreated patients develop full blown ARDS and MODS
involving hepatic dysfunction, respiratory failure, renal
failure and myocarditis
• The case fatality rate for untreated classic cases is 7%.

53. INVESTIGATIONS
• Rickettsiae are potential biohazard and require
high tech (BSL III) laboratory for culture facilities.
• Tests available are weil-felix test, indirect immuno
flurosence test, and ELISA test.
• ELISA is most sensitive and easily available test.
• IgM suggests recent infection.
• PCR can be done on blood sample and on biopsy
of rashes and tissues.

54. TREATMENT
• One should start the treatment as soon as possible on
suspicion of Rickettsial infection.
• All rickettsias are susceptible to tetracycline group and
Doxycycline is DOC.
• This is bacteriostatic.
• Given as 100mg twice a day.
• Fever subsides within 24-48 hours then given for 3-5
days more.
• If fever remains for 5-7 days then continued till 10
days.
• IV doxycycline can be used in sick and hospitalised
patients..
• Safe in children more than 6 years of age

55. • Chloramphenicol can be used as alternative drug
but its side effects and poorer antibacterial
activity limits its use.
• Tertacyclines cannot be used in pregnancy
because of malformations of teeth and bones in
fetus and hepatotoxicity and pancreatitis in
mothers.
• Chloramphenicol can be used in pregnancy
except in third trimester with fear of grey baby
syndrome.
• Rifampicin can be used safely in pregnancy.

56. • Strains resistant to tetracyclines and
chloramphenicol can be treated with
Aithromycin or Roxithromycin.
• Rifampicin can also be used.

57. REFERENCES
• HARRISSON’S PRINCIPLES OF INTERNAL
MEDICINE 20TH EDITION
• API TEXTBOOK OF MEDICINE 11TH EDITION

58. THANK YOU